1. Field of the Invention
The present invention is in the field of pharmaceutical compositions and methods of using the same for the treatment of overactive bladder and reduction of various side effects thereof.
2. Description of the Related Art
Overactive bladder (OAB) is characterized by involuntary contractions of the detrusor muscle during bladder filling. These contractions may be asymptomatic or may cause the three common symptoms that clinically define OAB: frequency of urination; urgency; and urge, or reflex, incontinence. Frequency is an increase in the number of micturitions, to as many as eight or more a day. Urgency is the strong and sudden desire to urinate. Urge incontinence, or reflex incontinence, is the situation where the urge to urinate cannot be controlled. Nocturia, or nighttime urinary frequency that disturbs sleep (more than twice a night), is often included as a fourth symptom. The symptoms of OAB may appear individually or together, and it is not known whether they have a pathologic or neurogenic cause.
Incontinence is present in over half of female patients with OAB. This condition affects more than 33 million Americans and imposes considerable economic, social, and psychological burdens. Although continued research in the pharmacologic management of lower urinary tract disorders have led to alternative treatment options, the symptoms of OAB are generally underreported by patients and under-treated by healthcare professionals.
Several classes of medications have been used to treat and manage OAB, including calcium channel blockers, tricyclic antidepressants, alpha-adrenergic antagonists, estrogen, and anticholinergic agents. Anticholinergic agents, which exert their effects at muscarinic receptors and suppress or diminish the intensity of involuntary detrusor muscle contractions, are the first-choice pharmacotherapy for OAB, and may be the only therapy available whose efficacy is not in question. Oxybutynin chloride and tolterodine tartrate are the most extensively studied of the anticholinergic agents, and the most widely used. A recent evidence-based systematic review of controlled clinical trials of several agents concluded that anticholinergic therapies significantly improved several indices of lower urinary tract function, including frequency of micturition and number of incontinence episodes. A major limitation of these agents is that they lack specificity for bladder tissue, with resultant bothersome side effects such as dry mouth and constipation.
Tolterodine has generally been associated with less dry mouth than oxybutynin. This property is thought to be due to the decreased selectivity of tolterodine for any one of the 5 muscarinic receptor subtypes (M1-M5), such as the M3 receptor that predominates in parotid tissue. Oxybutynin, more than tolterodine, has a high affinity for this receptor, which also mediates bladder contraction. It has been argued on the basis of animal data that tolterodine has a greater selectivity than oxybutynin for bladder than for parotid muscarinic receptors, but such a mechanism remains to be elucidated. Effects on M2 receptors, which populate bladder smooth muscle though not glandular tissue, and for which tolterodine shows a greater affinity than oxybutynin, have also been invoked to explain the relatively slightly lower degree of dry mouth that is associated with the therapeutic effect of tolterodine.
Additional reports that the higher extent of dry mouth with oxybutynin is attributed to formation of the major metabolite, desethyloxybutynin, which appears to have a greater affinity for the M3 subtype receptors also expressed in the salivary glands. However, the newer extended-release formulations of oxybutynin and tolterodine provide comparable or perhaps slightly better efficacy and enhanced tolerability compared with immediate-release formulations. More recently approved agents including trospium chloride, solifenacin succinate (Vesicare) and darifenacin (Enablex) appear to have a better side effect profile, i.e., slightly less dry mouth. Nonetheless, the dry mouth and constipation continue to be problematic and patients stop taking the medication after short period of therapy.
Thus, there exists a need in the art for a medication that provides sufficient efficacy for the treatment of OAB, with much reduced level of side effects in order to increase patient compliance, comfort, and efficacy.